Dextran (C.sub.6 H.sub.10 O.sub.5)n is a polysaccharide polymer, containing a plurality of mainly alpha-1,6 linked glucopyranose or glucosyl units, obtained by the action of certain organisms upon sucrose by methods well known to the prior art. It is generally produced in the form of an aqueous solution of a mixture of polymers of various molecular weights.
Iron dextran has been developed and utilized as a satisfactory product for therapeutic use, primarily as an agent for correcting iron deficiencies in animals and humans by parenteral administration as by intravenous or intramuscular injection. This product has certain advantages deriving from low toxicity, low incidence of side reactions and effective rate of iron absorption. It is frequently prepared by forming a complex of dextran with colloidal ferric hydroxide.
Certain prior art patents describe ferric hydroxide complexes with dextran or other carbohydrate derivatives in efforts to achieve a desired high iron content, suitable stability and low toxicity. Illustrative of such art are U.S. Pat. No. 3,536,696 to Alsop and Bremner and British Pat. No. 1,200,902 to the same inventors. Their U.S. patent describes the formation of ferric hydroxide complexes with a dextran carboxylic acid formed by introducing a carboxylic acid group into a terminal unit of the dextran polymer to form a dextran heptonic acid. The Alsop et al. British patent relates to a procedure for forming the ferric hydroxide complex by controlling the rate of addition of alkali during complexing.
One disadvantage of conventional iron dextran complexes is the fact that it is difficult to obtain injectable stable complexes in colloidal solution with fairly high iron content; say more than 10%, and that as the iron content increases, the viscosity of the complex increases rapidly so that at higher iron content the higher viscosity impedes administration by injection and decreases the rate of absorption into animal tissues.
As described in U.S. Pat. No. 4,370,476, high iron dextran complexes are obtained by reacting dextran in a two stage oxidation process to produce a polycarboxylic acid dextran polymer which is then complexed with ferric hydroxide to obtain a stable colloidal solution compound of very fine particles of ferric hydroxide as a complex with the dextran polymer in which the elemental iron content may be from 10-20% or more.
Prior to the above mentioned patent, an attempt was made to produce stable ferric hydroxide complexes having a ferric iron content of over 10% by reacting the ferric hydroxide with a dextran polymer which had been modified by treatment with sodium hydroxide at elevated temperatures to produce a product which was alleged to include a dextran polymer having a carboxylic acid group formed on at least one terminal unit of the polymer. While such structure may have been formed in this reaction, it was also discovered that the alkali simultaneously attacked the dextran polymer to produce a number of low molecular weight and colored breakdown products which were difficult if not impossible to separate and which would prevent practical separation of the carboxylic acid derivative for complexing with iron.
This process is described in British Pat. No. 1199951, and although the example does describe a product having an iron content of 15.4%, as a practical matter it was found that complexes suitable for injection having an iron content of over 10% could not be achieved without extensive and impractical purification procedures which also reduced yields to non-commerical levels.
Inasmuch as the dextran polymer of commerce is in fact a mixture of polymers of various molecular weights, it was apparent that reaction with alkali would not be effective to introduce a substantial number of carboxylic acid groups into the polymer mixture to facilitate introduction of ferric iron into the complex to effect the desired increase in iron content.
Subsequently, the difficulties apparently encountered in the practice of the process of the aforesaid British Pat. No. 1199951 led to the development of the process and product described in U.S. Pat. No. 3,536,696, in which dextran was first converted to a heptonic acid derivative and then complexed with ferric hydroxide. Complexes containing up to 250 mg of elemental iron per ml of solution are stated to be obtained. While this process appears to be effective in producing high iron content complexes, it does entail the use of cyanides to produce the heptonic acid derivative with its consequent disadvantages.